Estrogen reportedly influences neurogenesis (new neuron formation) and neuronal survival of progenitor cells in the adult female rat hippocampal dentate gyrus (DG). While 17beta-estradiol (E2) is believed to be the estrogen subserving such functions, its little studied and largely ignored, natural steroisomer, 17alpha-E2 may be the more important estrogen for the brain. This proposal tests the hypothesis that 17alpha-E2 and ER-X, its plasma-membrane -associated receptor, and not the traditional 17beta-E2/nuclear ER-alpha and ER-beta receptor systems, mediate the effects of estrogen on neurogenesis and neuronal survival. This hypothesis is based on our observations that the en dogenous content of 17alpha-E2 i n the adult hippocampal DG is significantly higher than that of 17beta-E2 and that adult hippocampal progenitor cells have high levels of "ER-X", while deficient in ER-alpha and ER-beta. This suggests that 17alpha-E2 has a crucial role in the hippocampal DG throughout life. This proposal consists of a series of correlative and complementary in vitro and in vivo experiments to compare the roles of 17alpha-E2 and 17beta-E2 in neurogenesis and neuronal survival, following an ischemic stroke, of the progenitor cells of the hippocampal DG of variously-aged C57BL/6J and 129/SvEV intact and ovariectomized (OVX) female mice, and other genotypes, including ER-alpha null, the aromatase knockout (ArKO) and transgenic Alsheimer's mice. Expression of ER-X in adult progenitor cells suggests that 17alpha-E2, its specific ligand, may have therapeutic potential for aging and neurodegenerative disorders. Absent circulating 17alpha-E2 levels, 17alpha-E2 and "ER-X" are unlikely to be part of a classical endocrine hormone/receptor system but may be synthesized locally and have important autocrine/paracrine brain functions. The therapeutic challenge is to discover how to stimulate and manipulate the endogenous progenitor cells, and how to make clinical use of the potential benefits of the elevated endogenous brain content of 17alpha-E2. The results will lead to drug design and therapeutic intervention without fear of undesirable peripheral effects mediated by ER-alpha or ER-beta, with enormous implications for safer hormone replacement strategies at the menopause and in the treatment of such neurodegenerative disorders as Alzheimer's disease and ischemic stroke, and psychiatric disorders such as major depression which accompanies such disorders frequently.